We classified a population of 34159 paired FT4 & TSH test results by combination of their reference ranges. This defined 9 classes with class specific hormonal ranges and the correlation between them. FT4 of a case alone can identify its class because the FT4 of a class has significant mean difference from all the rest 8 classes (sig <.002) except in 2 specific situations which can be solved by their TSH (sig.000). There is no strong association between FT4 and TSH in any of our class(r < .445) and so it warns not to use TSH alone in diagnostic or follow-up settings. We opine to use of the reference of FT4 of euthyroid class as the treatment target for all cases with abnormal functional status and it has the potential to resolve some pitfalls in thyroid medicine.
Like elsewhere, the major bulk of tests in our Endocrinology laboratory are Thyroid Function Tests. This is due to increased loads from three different areas - namely a) lifelong follow-up of thyroid patients; b) increasing pull of diagnostic tests for new clinical cases and c) screening protocols of thyroid function status of apparently asymptomatic people as in i) routine workup of growth and development, infertility services, ii) health checks of increased number of cancer survivors and senior citizens.
Initially with T4 and or T3 and then FT4 and or FT3 value the people under investigation could be grouped into 3 functional status - euthyroximia (normal), hypothyroximia (hypofuncting) or hyperthyroximia (hyperfuncting). Subsequently with the introduction of TSH measurement it was found that the majority but not all people with euthyroximia, hypothyroximia and hyperthyroximia were coupled with normal, high and low TSH respectively. This concordance between hormones from thyroid and pituitary gland has enlightened us on the status of thyropituitary axis in disease state. A conclusion was made - hypothyroximia and hyperthyroximia in concordance states are due to abnormality at thyroid level without any abnormality at pituitary (Thyrotrop) level or above. They were named as primary hypothyroidism and primary hyperthyroism respectively. On the other hand, the discordant population consists of diverse pathology at and/or above pituitary and which may even encompass abnormality at thyroid level.
This subset, though relatively rare, became the real challenge in thyroid medicine.
In our present study, we used the existing reference ranges together (paired) to classify biochemical status. In total there are 9 classes of which 3 (including the normal) have with concordance and rest 6 with discordance pair of FT4 and TSH (Figure 1). This system of classification has the capacity to put any paired value into its class and so can be said to have 360° capability. The mean difference (MD) between the hormones of classes in all the 36 possible pairs was determined. This proved, FT4 of a class is distinct from all the rest 8 classes with significant MDs (sig < 0.002); but two exceptions - namely.
1) Between primary hypothyroid and isolated hypothyroximia classes; MD sig .228.
2) Between secondary hyperthyroidism and Isolated Hyperthyroximia classes; MD sig .872.
And both the pairs have distinct TSH (MD, sig.000). So, this system of classification is capable of defining functional status (class) of an individual by his/her FT4 result only except for 2 specific pairs and in those situations a TSH value resolves the issue (see Figure 3 of the original article).
The reference population for normal thyroid function (euthyroidism) in this study consists of 24722 cases. The normograms of their FT4 and TSH are of almost bell shape and 95% CI of means are (14.83-14.90 pmol/ml) and (2.40 – 2.43mIU/ml) respectively (see Figures 1 and 2) and by Cohen’s standard there is no association between the two hormones (r -0.056; sig.000) in it. We did cohort analysis to verify this nature of association. Cohorts are as follows with their correlation coefficients expressed as r value (2 tail significance) (pupation):
1) Cohorts on time of data collect (3 series ), series 1(first 12 months) -0.041(.000) (n-8694), series 2 (next 6 months) -0.028(0.013) (n-7772) and series 3(last 6 months) -0.090(.000) (n-8256);
2) Cohorts on age groups adult-0.102(0.000)(n-19240), Children-0.051(0.001) (n-3950), Infants-0.041(0.170) (n-1147) & Neonates-0.066(0.198) (n-385) and
3) Cohorts on sex - male-0.010(0.373) (n-7708) & female-0.088(0.000) (n-17014). See Figure 2.
So, in all our cohorts there is no association between the 2 hormones (r <. 088) and only except in adult age cohort where r value is 0.102 which is just on the cut point between no association and weak association. We therefore, hypothesized that there exist a silent phase of Thyro-pituitary axis during the state of metabolic equilibrium (euthyroidism) and it starts operating in a negative feedback fashion when equilibrium is lost. The FT4 of our primary hypothyroid and primary hyperthyroid classes are (6.82-7.09 pmol/ml) & (35.59-38.45 pmol/ml) respectively. And their r values with TSH are (-.445, sig.000; n 783) & (-.386, sig.000; n 564) and so it supports the hypothesis.
There is no strong association between the two hormones in our total study population (r-0.261, sig.000; n 34159) or in any of its 9 class (r < 0.445; sig.000). Therefore, any attempt to use value of one hormone to assume the status of the other one is not valid. Consequences of such an effort may even
lead to discontinuation of replacement therapy and lost from follow-up. This is not an uncommon finding in practice by non thyroidologist. To my experience it happens more with hypothyroid pregnant ladies .
The reference range of both FT4 and TSH are calculated from data of clinically euthyroid population. There are 4 separate (age specific) ranges for TSH and but only one for FT4. We used them in pair and they yield classes with class specific hormonal ranges and the correlation between them. So a class defined by this system exploits/incorporates status of the thyropituitary axis of the class. Such a system has ability to pick up biochemically more homogeneous cases than done by one hormone. In follow up setting this classification will provide data on phenomenon of shift of functional status of a case by therapeutic intervention and/or by the course of natural process. We expect that this system of classification will enable us to reduce pitfalls that exist in thyroid medicine [2-11].
In the present system of classification FT4 alone is capable of determining the functional status/class of a person in 34 out total 36 paired settings between its 9 classes. And the rest 2 settings are solved by their TSH. We expect that all laboratories will publish their data using the new system of classification and that will enable us to adopt at least three simple strategies in thyroid medicine. They are:
Strategy 1 and 2 will make lifelong thyroid health care more cost-effective. Data generated by the strategy 3 will be valuable source to develop cost-effective management protocols for common, uncommon and rare cases with abnormal thyroid function in near future.
We believe that immediate useful output of our study is the target of single biochemical goal for all thyroid cases with abnormal function. We opine that future trends of research should focus on search of aetiology/cause(s) for individual class and the cumulative data of such studies will help us to
understand the phenomenon of shifting of functional status of cases with particular aetiology, to simplify diagnostic and therapeutic workups and also to develop better management protocols for common as well as rare & emerging disorders in thyroid medicine.
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